The present invention relates to benzodiazepine derivatives having an important role in a medical field. More specifically, the invention relates to calcium salts of 1,5-benzodiazepine derivatives having a gastrin and/or CCK-B (cholecystokinin-B) receptor antagonism and at the same time having potent gastric acid secretion inhibitory action; preparation processes of the compounds; and drugs containing the compounds as an effective ingredient.
Cholecystokinin (CCK) is a gastrointestinal hormone which is produced by and released from duodenal and jejunal mucous membranes, and is known to have actions such as secretion of pancreatic juice, gallbladder constriction, and stimulation of insulin secretion. CCK is also known to be present in the cerebral cortex, hypothalamus, and hippocampus at a high concentration and exhibit actions such as inhibition of eating and hunger, augmentation of memory, and generation of anxiety. Gastrin is a gastrointestinal hormone which is produced by and released from G-cells distributed in the pylorus and is known to exhibit actions such as secretion of gastric acid and constriction of the pylorus and gallbladder. CCK and gastrin, having the same five amino acids in their C-terminals, express actions via receptors. CCK receptors are classified into CCK-A which are peripheral type receptors distributed in the pancreas, gallbladder, and intestines; and CCK-B which are central type receptors distributed in the brain. Since gastrin receptors and CCK-B receptors show similar properties in receptor-binding tests and have high homology, they are often called CCK-B/gastrin receptors. Compounds having antagonism to these receptors, for example, gastrin or CCK-B receptor, are presumed to be useful for prevention or treatment of gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, pancreatitis, Zollinger-Ellison syndrome, vacuolating G-cell hyperplasia, basal-mucous-membrane hyperplasia, cholecystitis, attack of biliary colic, dysmotilities of alimentary canal, irritable bowel syndrome, certain types of tumors, eating disorders, anxiety, panic disorder, depression, schizophrenia, Parkinson""s disease, tardive dyskinesia, Gilles de la Tourette syndrome, drug dependence, and drug-withdrawal symptoms. Moreover, the compounds are expected to induce pain relief or to accelerate induction of pain relief by opioid medications (Folia Pharmacologica Japonica, Vol. 106, 171-180 (1995), Drugs of the Future, Vol. 18. 919-931 (1993), American Journal of Physiology, Vol. 269, G628-G646 (1995), American Journal of Physiology, Vol. 259, G184-G190 (1990), European Journal of Pharmacology, 261, 257-263 (1994), Trends in Pharmacological Science, Vol. 15, 65-66 (1994)).
As a gastrin receptor antagonist, proglumide is known as a remedy for gastric ulcer and gastritis. Proglumide""s affinity with gastrin or CCK-B receptors is however very low, and its curative effect is weak. It is reported that some benzodiazepine derivatives such as L-364,718 (devazepide, Japanese Patent Application Laid-Open (kokai) No. 63666/1986) and L-365,260 (Japanese Patent Application Laid-Open (kokai) No. 238069/1988) exhibit CCK-A receptor antagonism or CCK-B receptor antagonism. It is also disclosed that compounds having strong CCK-B receptor antagonism suppress pentagastrin-stimulated secretion of gastric acid (WO 94/438 and WO 95/18110). Administration in vivo of these compounds however does not always bring about satisfactory effects. In WO98/25911 and WO99/64403, the present inventors therefore disclosed 1,5-benzodiazepine derivatives having potent gastrin and/or CCK-B receptor antagonism and at the same time, having strong gastric acid secretion inhibitory action. There is however a demand for compounds which have potent gastrin and/or CCK-B receptor antagonism and gastric acid secretion inhibitory action, particularly strong in gastric acid secretion inhibitory action, and are suited for clinical use.
With the foregoing in view, the present inventors have carried out an extensive investigation. As a result, it has been found that compared with 1,5-benzodiazepine derivatives as specifically described in WO98/25911 and WO99/64403, calcium salts of 1,5-benzodiazepine derivatives having a specific structure, which salts fall within a range disclosed in WO98/25911 and WO99/64403 but are not specifically described therein, have markedly potent inhibitory activity against gastric acid secretion; and owing to low hygroscopicity and easy purification, are desirable as drugs from the viewpoint of quality maintenance so that they are useful as drugs, particularly preventives or remedies for various diseases of digestive tracts resulting from excessive secretion of gastric acid, leading to the completion of the invention.
In one aspect of the present invention, there are thus provided a calcium salt of a 1,5-benzodiazepine derivative represented by the following formula (I): 
(wherein, R1 represents a lower alkyl group, R2 represents a phenyl or cyclohexyl group, and Y represents a single bond or a lower alkylene group); and a preparation process of the calcium salt.
In another aspect of the invention, there is also provided a gastric acid secretion inhibitor, which comprises, as an effective ingredient, a calcium salt of a 1,5-benzodiazepine derivative represented by the formula (I).
In a further aspect of the invention, there is also provided a drug comprising, as an effective ingredient, a calcium salt of a 1,5-benzodiazepine derivative represented by the formula (I), particularly, a preventive or remedy for gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis or Zollinger-Ellison syndrome.
In a still further aspect of the invention, there is also provided a pharmaceutical composition comprising a calcium salt of a 1,5-benzodiazepine derivative represented by the formula (I) and a pharmaceutically acceptable carrier, particularly, a pharmaceutical composition for preventing and/or treating gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis or Zollinger-Ellison syndrome.
In a still further aspect of the present invention, there is also provided the use of a calcium salt of a 1,5-benzodiazepine derivative represented by the formula (I) for the preparation of a preventive and/or remedy for gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis or Zollinger-Ellison syndrome.
In a still further aspect of the present invention, there is also provided a treating method of gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis or Zollinger-Ellison syndrome, which comprises administering a calcium salt of a 1,5-benzodiazepine derivative represented by the formula (I).
The term xe2x80x9clowerxe2x80x9d as used herein means a linear or branched carbon chain having 1 to 4 carbon atoms.
Accordingly, examples of the xe2x80x9clower alkyl groupxe2x80x9d include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, while those of the xe2x80x9clower alkylene groupxe2x80x9d include methylene, ethylene, propylene, butylene, methylmethylene, dimethylmethylene, 1-methylethylene, 1,1-dimethylethylene, 1-methylpropylene and 2-methylpropylene.
The term xe2x80x9chalogen atomxe2x80x9d as used herein means a fluorine, chlorine, bromine or iodine atom.
The term xe2x80x9cmetal atomxe2x80x9d as used herein means a metal atom which can be converted into a monovalent or divalent cation and examples include sodium, potassium and calcium atoms.
It is preferred that in the formula (I), R1 represents a branched C4 alkyl group, particularly, a tert-butyl group; R2 represents a cyclohexyl group and Y represents a single bond or dimethylmethylene.
The present invention not only embraces optically active isomers and diastereomers but also solvates such as hydrates and polymorphs.
Of the invention compounds (I), particularly preferred from the viewpoint of inhibitory action against gastric acid secretion and storage stability are calcium (R)-(xe2x88x92)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoate (Compound of Example 1) and calcium (R)-(xe2x88x92)-2-[3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenyl]-2-methylpropionate (Compound of Example 4), with Compound of Example 1 being still more preferred.
The invention compounds (I) can be prepared by various synthesis processes in consideration of their essential skeleton or features of the constituent groups. The following are typical preparation processes of them. Preparation Process A: 
(wherein, R1, R2 and Y have the same meanings as described above, Boc represents a tert-butoxycarbonyl group and X represents a halogen atom).
Step A1
Reaction of a 3-substituted aminobenzodiazepine derivative (V) with cyclohexanone leads to preparation of the corresponding 5-substituted derivative (VI). For the preparation of the 5-substituted derivative (VI) having a cyclohexyl group as R2, a catalyst such as platinum oxide or palladium carbon is added to a solution of the derivative (V) dissolved in acetic acid, followed by stirring under normal pressure or under pressure in a hydrogen atmosphere. Usually, this reaction can be carried out at room temperature, under warming or under heating. For the preparation of a 5-substituted derivative (VI) having a phenyl group as R2, on the other hand, a hydrogen acceptor such as cyclooctene or nitrobenzene is added to the derivative (V) in a solventless manner or in a solvent inert to the reaction such as xylene, and then a catalyst such as palladium carbon is added, followed by stirring. Usually, this reaction can be carried out under warming or heating.
Step A2
Reaction of the 5-substituted derivative (VI) with a halomethyl ketone compound (VII) leads to preparation of the corresponding 1,5-substituted derivative (VIII). This reaction is usually conducted by adding a base such as sodium hydride, potassium carbonate or potassium tert-butoxide to the 5-substituted derivative (VI), adding the compound (VII) to the resulting mixture and then adding, if necessary, a phase transfer catalyst such as tetrabutylammonium bromide. For the reaction, any solvent inert to the reaction is usable. Usually employed is an ether solvent such as tetrahydrofuran or dioxane, toluene, ethyl acetate, N,N-dimethylformamide or dimethylsulfoxide. Alternatively, the reaction can be effected in a two phase system such as water-toluene in the presence of a phase transfer catalyst such as tetrabutylammonium bromide. The reaction is usually conducted within a temperature range of xe2x88x9278 to 150xc2x0 C.
Step A3
The 1,5-substituted derivative (VIII) can be converted into an oxalate (III) of a 3-amino-1,5-benzodiazepine derivative after deprotection. The deprotection is effected by adding an acid such as hydrochloric acid or trifluoroacetic acid to the derivative (VIII). This reaction is usually conducted in the presence or absence of a solvent within a temperature range of from 0 to 100xc2x0 C. Examples of the solvent usable here include alcohols such as methanol and ethanol, halogen solvents such as chloroform and ether solvents such as dioxane and diethyl ether. The subsequent conversion into an oxalate is conducted in a manner known per se in the art by adding oxalic acid or hydrate thereof to the hydrolyzate obtained by the above-described reaction.
Step A4
Reaction of the oxalate (III) of a 3-amino-1,5-benzodiazepine derivative with Compound (IV) leads to preparation of the corresponding 1,5-benzodiazepine derivative (II). This reaction is usually conducted in the presence or absence of a base such as triethylamine within a range of 0xc2x0 C. to reflux temperature. For the reaction, any solvent inert to the reaction can be used and N,N-dimethylformamide or dimethylsulfoxide is usually employed.
Step A5
Aqueous ammonia is then added to the 1,5-benzodiazepine derivative (II), followed by treatment of the mixture by adding thereto a calcium chloride solution, whereby the invention compound (I) can be prepared. This reaction is usually conducted by adding aqueous ammonia under ice cooling, at room temperature, under warming or under heating; stirring the mixture; and then adding a calcium chloride solution. For this reaction, any solvent one inert to the reaction can be used and ethanol is usually employed.
Preparation Process B 
(wherein, R1, R2 and Y have the same meanings as described above, R3 represents a hydrogen atom or a metal atom and X represents a halogen atom).
Step B1
Reaction of the oxalate (III) of a 3-amino-1,5-benzodiazepine derivative with Compound (IX) leads to preparation of the corresponding 3-phenoxycarbonylamino derivative (X). This reaction is usually conducted under ice cooling, at room temperature, under warming or under heating in the presence or absence of a base such as potassium carbonate or triethylamine. For the reaction, any solvent inert to the reaction is usable and ethyl acetate, tetrahydrofuran or N,N-dimethylformamide is usually employed.
Step B2
By adding an aniline derivative (XI) to the 3-phenoxycarbonylamino phenoxycarbonylamino derivative (X), the corresponding 1,5-benzodiazepine derivative (II) can be prepared. This reaction is usually carried out in the presence or absence of a base such as triethylamine or potassium carbonate within a range of 0xc2x0 C. to reflux temperature. For the reaction, any solvent inert to the reaction is usable and usually employed is dimethylsulfoxide or N,N-dimethylformamide.
The 1,5-benzodiazepine derivative (II) obtained in Step B2 can be introduced into the invention compound (I) in accordance with step A5 of Preparation Process A.
The invention compound (I) thus prepared is isolated and then purified by the ordinarily employed operation selected as needed from extraction, concentration, evaporation, crystallization, filtration, recrystallization, pulverization, and chromatography. The optically active invention compound (I) can be produced using a proper raw material compound, or by ordinarily employed racemic resolution method such as a method of introducing the compound into the corresponding diastereomer salt with a typical optically active acid such as dibenzoyl tartrate, followed by optical resolution; or a method of introducing the compound into the corresponding diastereomer compound, separating it and then subjecting the separated compound to Edman degradation.
The invention compound (I) can be administered orally or parenterally after incorporation therein a pharmaceutically acceptable carrier or adjuvant. For oral administration, the compound of the present invention may be formed into solid preparations such as tablets, powder, and capsules by using, in combination, proper additives, for example, excipients such as lactose, mannitol, corn starch, and crystalline cellulose; binders such as cellulose derivatives, gum arabic, and gelatin; disintegrators such as carboxymethyl cellulose calcium; lubricants such as talc and magnesium stearate. These solid preparations may be formed into enteric coating preparations by using a coating base such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate or methacrylate copolymer. Alternatively, they may be formed into liquid preparations such as solutions, suspensions, and emulsions.
For parenteral administration, the compound of the present invention may be formed into a liquid formulation for injection by using, in combination, water, ethanol, glycerin or ordinarily employed surfactant. It may also be formed into a suppository by using a suppository base.
The dose of the invention compound (I) varies depending on the dosage form, administration route, age, or symptoms. Orally, the dose is 1-1,000 mg, preferably 5-500 mg, per day for an adult and it is preferably administered once or 2 to 3 portions a day.
As described later, invention compounds (I) exhibit strong inhibitory action against secretion of gastric acid compared with the compounds as described in WO98/25911 and WO99/64403. In addition, they have low hygroscopicity and can be purified readily so that from the viewpoint of maintenance of its quality, they are excellent as a drug. Moreover, they exhibit potent antagonism against gastrin and/or CCK-B receptor, and therefore, they are useful for treatment, amelioration, or prevention of various diseases of digestive tracts resulting from excessive secretion of gastric acid, for example, gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, pancreatitis and Zollinger-Ellison syndrome. They are also useful for the treatment, amelioration or prevention of diseases related to gastrin and/or CCK-B receptor antagonism, such as vacuolating G-cell hyperplasia, basal-mucous-membrane hyperplasia, cholecystitis, attack of biliary colic, dysmotilities of alimentary canal, irritable bowel syndrome, certain types of tumors, eating disorders, anxiety, panic disorder, depression, schizophrenia, Parkinson""s disease, tardive dyskinesia, Gilles de la Tourette syndrome, drug dependence, and drug-withdrawal symptoms; and induction of pain relief or augmentation of induction of pain relief by an opioid medication.